CN113876721A - Preparation process of cefoperazone sodium and sulbactam sodium for injection - Google Patents
Preparation process of cefoperazone sodium and sulbactam sodium for injection Download PDFInfo
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- CN113876721A CN113876721A CN202111247416.XA CN202111247416A CN113876721A CN 113876721 A CN113876721 A CN 113876721A CN 202111247416 A CN202111247416 A CN 202111247416A CN 113876721 A CN113876721 A CN 113876721A
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- sodium
- cefoperazone
- sulbactam
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- NKZMPZCWBSWAOX-IBTYICNHSA-M Sulbactam sodium Chemical compound [Na+].O=S1(=O)C(C)(C)[C@H](C([O-])=O)N2C(=O)C[C@H]21 NKZMPZCWBSWAOX-IBTYICNHSA-M 0.000 title claims abstract description 102
- 229960000614 sulbactam sodium Drugs 0.000 title claims abstract description 102
- NCFTXMQPRQZFMZ-WERGMSTESA-M Cefoperazone sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C([O-])=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 NCFTXMQPRQZFMZ-WERGMSTESA-M 0.000 title claims abstract description 100
- 229960002417 cefoperazone sodium Drugs 0.000 title claims abstract description 100
- 238000002347 injection Methods 0.000 title claims abstract description 64
- 239000007924 injection Substances 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000007853 buffer solution Substances 0.000 claims abstract description 14
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims abstract description 11
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims abstract description 11
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 39
- 238000001914 filtration Methods 0.000 claims description 29
- 238000003756 stirring Methods 0.000 claims description 20
- 239000012528 membrane Substances 0.000 claims description 19
- 229960004682 cefoperazone Drugs 0.000 claims description 12
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 9
- 108090000204 Dipeptidase 1 Proteins 0.000 claims description 9
- 102000006635 beta-lactamase Human genes 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000000600 sorbitol Substances 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 239000008055 phosphate buffer solution Substances 0.000 claims description 5
- 241000894006 Bacteria Species 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 238000004042 decolorization Methods 0.000 claims 2
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- 206010059866 Drug resistance Diseases 0.000 abstract description 9
- 239000012535 impurity Substances 0.000 abstract description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 4
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- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract description 3
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- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 2
- 208000011117 substance-related disease Diseases 0.000 abstract description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 18
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- 229930186147 Cephalosporin Natural products 0.000 description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 2
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- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
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- 206010061695 Biliary tract infection Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
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- 239000003242 anti bacterial agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
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- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- 229960002727 cefotaxime sodium Drugs 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
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- 238000000576 coating method Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- -1 lactam compounds Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229960000373 tazobactam sodium Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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Abstract
The invention provides a preparation process of cefoperazone sodium and sulbactam sodium for injection, which comprises the steps of dissolving cefoperazone sodium and sulbactam sodium by using a solvent simultaneously, adding a phosphoric acid buffer solution to adjust the pH value, improving the mixing degree and stability of cefoperazone sodium and sulbactam sodium, and avoiding introducing new impurities; by adding histidine and leucine, the curative effect of cefoperazone sodium and sulbactam sodium is improved, the use amount of cefoperazone sodium and sulbactam sodium is reduced, and the situation of increased drug resistance of strains caused by drug abuse is reduced.
Description
Technical Field
The invention relates to the technical field of medicinal preparations, in particular to a preparation process of cefoperazone sodium and sulbactam sodium for injection.
Background
The cefoperazone sodium and sulbactam sodium are a compound preparation. Sulbactam sodium is an irreversible competitive beta-lactamase inhibitor which is artificially synthesized, and is usually combined with penicillin and cephalosporin medicaments, so that the sulbactam sodium is prevented from being damaged by the beta-lactamase, and the antibacterial activity is enhanced. Cefoperazone sodium is the third generation cephalosporin and has bacteriostatic action on most gram-positive anaerobic bacteria and some gram-negative anaerobic bacteria. However, the relative stability of cefoperazone sodium to beta-lactamase is poor, the combination of cefoperazone sodium and sulbactam sodium not only shows obvious synergistic antibacterial activity to negative bacilli, but also has antibacterial action 4 times of that of cefoperazone after combination. The cefoperazone sodium and sulbactam sodium is mainly used for treating respiratory system and genitourinary system infection, peritonitis, cholecystitis, biliary tract infection, intraperitoneal infection, septicemia and the like caused by sensitive bacteria.
Because cefoperazone sodium and sulbactam sodium are both lactam compounds, unstable beta-lactam rings are contained in chemical structures, hydrolysis and degradation are easy, and degradation and polymerization reactions often occur due to thermal instability in the storage process, so that the content of active ingredients of the medicine is reduced, and impurities are increased.
Chinese patent CN101284009 discloses a cefoperazone sodium and sulbactam sodium composition and a preparation method thereof, and sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium chloride are added in a prescription, so that the stability of the compound preparation can be greatly improved, and the product can be guaranteed to be qualified in the valid period by storing in a cool and dark dry place.
Chinese patent CN104644640A discloses a method for preparing cefoperazone sodium and sulbactam sodium powder injection for injection, which utilizes a solid mass transfer column plate technology to prepare a recovered solvent, and the recovered solvent is directly applied to the production of cefoperazone sodium and sulbactam sodium products, and the obtained cefoperazone sodium and sulbactam sodium powder injection product for injection has greatly improved quality indexes such as color grade, clarity, purity and the like, high quality stability and less impurities.
The method solves the problem of storage stability of the cefoperazone sodium and sulbactam sodium, but in recent years, with the large use of the cefoperazone sodium and sulbactam sodium, the clinical common gram-negative bacteria have certain drug resistance to the cefoperazone sodium and the clinical curative effect is reduced.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation process of cefoperazone sodium and sulbactam sodium for injection.
The invention relates to a preparation process of cefoperazone sodium and sulbactam sodium for injection, which comprises the following steps:
s1, dissolving cefoperazone sodium and sulbactam sodium by using a solvent, adding a buffer solution at the temperature of 20 +/-5 ℃, stirring for dissolving, and filtering to obtain a cefoperazone sodium-sulbactam sodium mixed solution;
s2, adding auxiliary materials into the solution obtained in the step S1, decoloring with activated carbon, and filtering with a microporous filter membrane after decoloring;
s3, controlling the temperature to be 20 +/-5 ℃ and the vacuum degree to be 0.058-0.073 MPa, then adding amino acid into the filtrate filtered in the step S2, stirring until the solution is clear, standing for 0.5-1 h, recovering to normal pressure, and filtering by using a microporous filter membrane to obtain a cefoperazone sodium and sulbactam sodium solution for injection;
s4, freeze-drying the cefoperazone sodium and sulbactam sodium solution for injection, and then carrying out aseptic split charging to obtain the cefoperazone sodium and sulbactam sodium for injection.
Further, the solvent is water and/or methanol.
Further, the mass-volume ratio of the cefoperazone sodium to the solvent is 1 g: 10-15 mL.
Further, the buffer solution is a phosphate buffer solution with a pH value of 5.5-6.5.
Further, the mass-to-volume ratio of the cefoperazone sodium to the buffer solution is 1 g: 5-6 mL.
Further, the auxiliary material is at least one of mannitol and sorbitol.
Furthermore, the dosage of the auxiliary material is 3-5 times of the mass of the cefoperazone sodium.
Further, the mass ratio of the cefoperazone sodium to the sulbactam sodium to the amino acid is (1-3): 1: 0.6 to 0.8.
Further, the amino acid is histidine and/or leucine.
Furthermore, the temperature of the freeze drying is-5 to 4 ℃, and the vacuum degree is-0.095 to-0.085 MPa.
Further, the cefoperazone sodium and sulbactam sodium for injection is applied to the preparation of medicines for treating infectious diseases caused by beta-lactamase producing bacteria.
Compared with the prior art, the invention has the beneficial effects that:
the cefoperazone sodium and sulbactam sodium preparation for injection is prepared by dissolving cefoperazone sodium and sulbactam sodium simultaneously with a solvent, and then adding a phosphoric acid buffer solution to adjust the pH value, so that the mixing degree and stability of cefoperazone sodium and sulbactam sodium are improved, and new impurities are prevented from being introduced.
The invention discovers that the addition of histidine and leucine can promote the combination of cefoperazone sodium and target protein of pathogenic strains, has synergistic effect with sulbactam sodium in inhibiting beta-lactamase, can improve the curative effect of cefoperazone sodium and sulbactam sodium preparations, reduce the use amount of cefoperazone sodium and sulbactam sodium, and reduce the situation of strain drug resistance increase caused by drug abuse.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
Example 1
A preparation process of cefoperazone sodium and sulbactam sodium for injection comprises the following steps:
s1, dissolving 1g of cefoperazone sodium and 0.5g of sulbactam sodium in 10mL of water, adding a phosphate buffer solution with the pH value of 5 mL6.5 at the temperature of 20 +/-5 ℃, stirring, dissolving and filtering to obtain a cefoperazone sodium-sulbactam sodium mixed solution;
s2, adding 3g of mannitol into the solution obtained in the step S1, decoloring by using activated carbon, and filtering by using a microporous filter membrane after decoloring;
s3, controlling the temperature to be 20 +/-5 ℃ and the vacuum degree to be 0.058MPa, then adding 0.6g of leucine into the filtrate filtered in the step S2, stirring until the mixture is clear, standing for 0.5-1 h, recovering to normal pressure, and filtering by using a microporous filter membrane to obtain a cefoperazone sodium and sulbactam sodium solution for injection;
s4, taking the cefoperazone sodium and sulbactam sodium solution for injection, carrying out freeze drying at the temperature of 4 ℃ under the vacuum degree of-0.095 MPa, and then carrying out sterile subpackage to obtain the cefoperazone sodium and sulbactam sodium for injection.
Example 2
A preparation process of cefoperazone sodium and sulbactam sodium for injection comprises the following steps:
s1, dissolving 1g of cefoperazone sodium and 0.33g of sulbactam sodium in 13mL of methanol aqueous solution (methanol: water: 1:3), adding 6 mLphosphate buffer solution with the pH value of 6.0 at the temperature of 20 +/-5 ℃, stirring, dissolving and filtering to obtain a cefoperazone sodium-sulbactam sodium mixed solution;
s2, adding 4g of sorbitol into the solution obtained in the step S1, decoloring with activated carbon, and filtering with a microporous filter membrane after decoloring;
s3, controlling the temperature to be 20 +/-5 ℃ and the vacuum degree to be 0.065MPa, then adding 0.2g of histidine and 0.5g of leucine into the filtrate filtered in the step S2, stirring until the mixture is clear, standing for 0.5-1 h, recovering to normal pressure, and filtering by using a microporous filter membrane to obtain a cefoperazone sodium sulbactam sodium solution for injection;
s4, taking the cefoperazone sodium and sulbactam sodium solution for injection, carrying out freeze drying at the temperature of-4 ℃ and under the vacuum degree of-0.085 MPa, and then carrying out sterile subpackage to obtain the cefoperazone sodium and sulbactam sodium for injection.
Example 3
A preparation process of cefoperazone sodium and sulbactam sodium for injection comprises the following steps:
s1, dissolving 1g of cefoperazone sodium and 1g of sulbactam sodium by using 10mL of methanol, adding 6mL of phosphate buffer solution with the pH value of 5.5 at the temperature of 20 +/-5 ℃, stirring, dissolving and filtering to obtain a cefoperazone sodium-sulbactam sodium mixed solution;
s2, adding 5g of sorbitol into the solution obtained in the step S1, decoloring with activated carbon, and filtering with a microporous filter membrane after decoloring;
s3, controlling the temperature to be 20 +/-5 ℃ and the vacuum degree to be 0.058MPa, then adding 0.6g of histidine into the filtrate filtered in the step S2, stirring until the solution is clear, standing for 0.5-1 h, recovering to normal pressure, and filtering by using a microporous filter membrane to obtain a cefoperazone sodium and sulbactam sodium solution for injection;
s4, taking the cefoperazone sodium and sulbactam sodium solution for injection, carrying out freeze drying at the temperature of minus 5 ℃ and under the vacuum degree of minus 0.085MPa, and then carrying out aseptic split charging to obtain the cefoperazone sodium and sulbactam sodium for injection.
Example 4
A preparation process of cefoperazone sodium and sulbactam sodium for injection comprises the following steps:
s1, dissolving 1g of cefoperazone sodium and 0.33g of sulbactam sodium in 13mL of methanol aqueous solution (methanol: water: 1:3), adding 6 mLphosphate buffer solution with the pH value of 4.5 at the temperature of 20 +/-5 ℃, stirring, dissolving and filtering to obtain a cefoperazone sodium-sulbactam sodium mixed solution;
s2, adding 4g of sorbitol into the solution obtained in the step S1, decoloring with activated carbon, and filtering with a microporous filter membrane after decoloring;
s3, controlling the temperature to be 20 +/-5 ℃ and the vacuum degree to be 0.065MPa, then adding 0.2g of histidine and 0.5g of leucine into the filtrate filtered in the step S2, stirring until the mixture is clear, standing for 0.5-1 h, recovering to normal pressure, and filtering by using a microporous filter membrane to obtain a cefoperazone sodium sulbactam sodium solution for injection;
s4, taking the cefoperazone sodium and sulbactam sodium solution for injection, carrying out freeze drying at the temperature of-4 ℃ and under the vacuum degree of-0.085 MPa, and then carrying out sterile subpackage to obtain the cefoperazone sodium and sulbactam sodium for injection.
Example 5
A preparation process of cefoperazone sodium and sulbactam sodium for injection comprises the following steps:
s1, dissolving 1g of cefoperazone sodium and 0.33g of sulbactam sodium in 13mL of methanol aqueous solution (methanol: water: 1:3), adding 6 mLphosphate buffer solution with the pH value of 6.0 at the temperature of 20 +/-5 ℃, stirring, dissolving and filtering to obtain a cefoperazone sodium-sulbactam sodium mixed solution;
s2, adding 4g of sorbitol into the solution obtained in the step S1, decoloring with activated carbon, and filtering with a microporous filter membrane after decoloring;
s3, controlling the temperature to be 20 +/-5 ℃ and the vacuum degree to be 0.065MPa, then adding 0.4g of histidine and 0.5g of leucine into the filtrate filtered in the step S2, stirring until the mixture is clear, standing for 0.5-1 h, recovering to normal pressure, and filtering by using a microporous filter membrane to obtain a cefoperazone sodium sulbactam sodium solution for injection;
s4, taking the cefoperazone sodium and sulbactam sodium solution for injection, carrying out freeze drying at the temperature of-4 ℃ and under the vacuum degree of-0.085 MPa, and then carrying out sterile subpackage to obtain the cefoperazone sodium and sulbactam sodium for injection.
Example 6
A preparation process of cefoperazone sodium and sulbactam sodium for injection comprises the following steps:
s1, dissolving 1g of cefoperazone sodium and 0.33g of sulbactam sodium in 13mL of methanol aqueous solution (methanol: water: 1:3), adding 6 mLphosphate buffer solution with the pH value of 6.0 at the temperature of 20 +/-5 ℃, stirring, dissolving and filtering to obtain a cefoperazone sodium-sulbactam sodium mixed solution;
s2, adding 4g of sorbitol into the solution obtained in the step S1, decoloring with activated carbon, and filtering with a microporous filter membrane after decoloring;
s3, controlling the temperature to be 20 +/-5 ℃ and the vacuum degree to be 0.065MPa, then adding 0.2g of arginine and 0.5g of leucine into the filtrate filtered in the step S2, stirring until the mixture is clear, standing for 0.5-1 h, recovering to normal pressure, and filtering by using a microporous filter membrane to obtain a cefoperazone sodium sulbactam sodium solution for injection;
s4, taking the cefoperazone sodium and sulbactam sodium solution for injection, carrying out freeze drying at the temperature of-4 ℃ and under the vacuum degree of-0.085 MPa, and then carrying out sterile subpackage to obtain the cefoperazone sodium and sulbactam sodium for injection.
Example 7
A preparation process of cefoperazone sodium and sulbactam sodium for injection comprises the following steps:
s1, dissolving 1g of cefoperazone sodium and 0.33g of sulbactam sodium in 13mL of methanol aqueous solution (methanol: water: 1:3), adding 6 mLphosphate buffer solution with the pH value of 6.0 at the temperature of 20 +/-5 ℃, stirring, dissolving and filtering to obtain a cefoperazone sodium-sulbactam sodium mixed solution;
s2, adding 4g of sorbitol into the solution obtained in the step S1, decoloring with activated carbon, and filtering with a microporous filter membrane after decoloring;
s3, controlling the temperature to be 20 +/-5 ℃ and the vacuum degree to be 0.065MPa, then adding 0.2g of histidine and 0.5g of glutamic acid into the filtrate filtered in the step S2, stirring until the mixture is clear, standing for 0.5-1 h, recovering to normal pressure, and filtering by using a microporous filter membrane to obtain a cefoperazone sodium sulbactam sodium solution for injection;
s4, taking the cefoperazone sodium and sulbactam sodium solution for injection, carrying out freeze drying at the temperature of-4 ℃ and under the vacuum degree of-0.085 MPa, and then carrying out sterile subpackage to obtain the cefoperazone sodium and sulbactam sodium for injection.
Example 8
A preparation process of cefoperazone sodium and sulbactam sodium for injection comprises the following steps:
s1, dissolving 1g of cefoperazone sodium and 0.33g of sulbactam sodium in 13mL of methanol aqueous solution (methanol: water ═ 1:3), adding 6 mLphosphate buffer solution with the pH value of 6.0 at the temperature of 20 +/-5 ℃, stirring to dissolve clear, adding 4g of sorbitol, 0.2g of histidine and 0.5g of leucine, stirring again to dissolve clear, standing for 0.5-1 h, and filtering to obtain a cefoperazone sodium-sulbactam sodium mixed solution;
s2, decoloring the solution obtained in the step S1 by using activated carbon, filtering by using a microporous filter membrane after decoloring is finished, freeze-drying the filtrate at-4 ℃ under the vacuum degree of-0.085 MPa, and then performing aseptic split charging to obtain the cefoperazone sodium and sulbactam sodium for injection.
The drug resistance rate of common pathogenic bacteria to the cefoperazone sodium and sulbactam sodium for injection is determined, and the result is shown in table 1;
the determination method is carried out by adopting SCF150 drug sensitive paper sheet method according to the influence of different proportions of cefoperazone sodium/sulbactam on the in vitro antibacterial effect of gram-negative bacilli, Zhang Ying and 2015';
test strains: ATCC 15442 pseudomonas aeruginosa, ATCC 35281 klebsiella pneumoniae, ATCC019606 acinetobacter baumannii;
TABLE 1 drug resistance Rate
As can be seen from Table 1, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii have lower drug resistance rate to cefoperazone sodium and sulbactam sodium for injection prepared by the invention, wherein the drug resistance rate of example 2 is the lowest.
Examples 6 to 7 show that the effect of reducing drug resistance is not good when histidine, leucine and other amino acids are used in combination with example 2.
Compared with example 2, example 8 shows that the preparation method of cefoperazone sodium and sulbactam sodium for injection of the invention also has influence on the drug resistance of strains.
Test examples quality test
Respectively measuring the quality indexes of the cefoperazone sodium and sulbactam sodium for injection under the conditions of cool and dark drying and low-temperature storage, wherein the measurement items comprise content, bacterial endotoxin, related impurities and relative hydrolysis rate, and the measurement methods of other items are carried out according to the related method under the item of cefoperazone sodium and sulbactam sodium for injection in Chinese pharmacopoeia second part (2020 edition) except the relative hydrolysis rate;
determination of relative hydrolysis ratio: the method is carried out according to a determination method of 'a stability test of cefotaxime sodium tazobactam sodium for injection on beta-lactamase, Lu-Guanwen, 2011', and specifically comprises the following steps:
1. extraction of beta-lactamase: selecting pseudomonas aeruginosa, inoculating the pseudomonas aeruginosa in 2.5ml of fresh M.H broth, culturing overnight at 37 ℃, sucking 2ml of the culture solution, adding the culture solution into 200ml of M.H broth, performing rotary shaking culture at 37 ℃ for 18h, centrifuging at 4 ℃ and 7000rpm for 10min, collecting thalli, washing the thalli for 2 times by using phosphate buffer solution (50Mm) with pHwei 7.0, repeatedly centrifuging, then preparing bacterial suspension by using phosphate solution, performing ultrasonic crushing under ice bath condition until the bacterial solution is clear, centrifuging at 4 ℃ and 10000rpm for 30min, collecting supernatant, obtaining beta-lactamase extracting solution, and identifying by using a Nitrocefin paper sheet;
2. determination of relative hydrolysis ratio: the method comprises the following steps of selecting a bacillus subtilis suspension as an indicator, selecting an antibiotic No. 1 as a culture medium, taking substrates as examples 1-8, preparing 8 substrates into solutions with the concentration of 16mg/L, setting 3 substrates to be parallel, taking 1.5mL of substrate solution, adding 20 mu L of beta-lactamase extracting solution, uniformly mixing, placing in a 37 ℃ water bath for reaction for 15min, coating the reacted mixed solution in reaction holes of an agar plate containing bacillus subtilis, processing at 37 ℃ for 14-16 h by 20 mu L of each hole, measuring antibacterial rings, obtaining the content of corresponding reaction substrates according to a standard curve, and calculating the relative hydrolysis rate;
3. standard curve: the substrates are prepared into substrate concentrations of 0mg/L, 2mg/L, 4mg/L, 8 mg/L and 16mg/L, the size of the inhibition ring is measured according to the method, and a standard curve is drawn.
TABLE 2 quality test results
The results show that the cefoperazone and sulbactam contents in the cefoperazone sodium and sulbactam sodium preparation for injection prepared by the invention meet the requirements, the bacterial endotoxin is in a specified range, the content and the relative hydrolysis rate of the relevant substances of the preparation prepared in example 2 are lower, the relative hydrolysis rates of the preparations prepared in examples 6-7 are high, and the content of the relevant substances of the preparation prepared in example 8 is high.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (9)
1. A preparation process of cefoperazone sodium and sulbactam sodium for injection is characterized by comprising the following steps:
s1, dissolving cefoperazone sodium and sulbactam sodium by using a solvent, adding a buffer solution at the temperature of 20 +/-5 ℃, stirring for dissolving, and filtering to obtain a cefoperazone sodium-sulbactam sodium mixed solution;
s2, adding auxiliary materials into the solution obtained in the step S1, performing decolorization treatment, and filtering with a microporous filter membrane after the decolorization is finished;
s3, controlling the temperature to be 20 +/-5 ℃ and the vacuum degree to be 0.058-0.073 MPa, then adding amino acid into the filtrate filtered in the step S2, stirring until the solution is clear, standing for 0.5-1 h, recovering to normal pressure, and filtering by using a microporous filter membrane to obtain a cefoperazone sodium and sulbactam sodium solution for injection; the amino acid is histidine and/or leucine;
s4, freeze-drying the cefoperazone sodium and sulbactam sodium solution for injection, and then carrying out aseptic split charging to obtain the cefoperazone sodium and sulbactam sodium for injection.
2. The process for preparing cefoperazone sodium and sulbactam sodium for injection according to claim 1, wherein the solvent is water and/or methanol.
3. The process for preparing cefoperazone sodium and sulbactam sodium for injection according to claim 2, wherein the mass-to-volume ratio of cefoperazone sodium to the solvent is 1 g: 10-15 mL.
4. The process for preparing cefoperazone sodium and sulbactam sodium for injection according to claim 1, wherein the buffer solution is phosphate buffer solution with pH value of 5.5-6.5.
5. The process for preparing cefoperazone sodium and sulbactam sodium for injection according to claim 4, wherein the mass-to-volume ratio of the cefoperazone sodium to the buffer solution is 1 g: 5-6 mL.
6. The process for preparing cefoperazone sodium and sulbactam sodium for injection according to claim 1, wherein the adjuvant is at least one of mannitol and sorbitol; the dosage of the auxiliary material is 3-5 times of the mass of the cefoperazone sodium.
7. The process for preparing cefoperazone sodium and sulbactam sodium for injection according to claim 1, wherein the mass ratio of cefoperazone sodium to sulbactam sodium to amino acid is (1-3): 1: 0.6 to 0.8.
8. The process for preparing cefoperazone sodium and sulbactam sodium for injection according to claim 1, wherein the temperature of freeze drying is-5 to 4 ℃, and the vacuum degree is-0.095 to-0.085 MPa.
9. Use of cefoperazone sodium sulbactam sodium for injection according to any one of claims 1 to 8, in the manufacture of a medicament for the treatment of infectious diseases caused by β -lactamase producing bacteria.
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| CN101284009A (en) * | 2008-05-29 | 2008-10-15 | 管小明 | Cefoperazone sodium and sulbactam sodium combination and preparation method thereof |
| CN102462684A (en) * | 2010-11-10 | 2012-05-23 | 湘北威尔曼制药股份有限公司 | Medicinal composition consisting of ceftriaxone sodium and sulbactam sodium and preparation method thereof |
| CN110893232A (en) * | 2019-09-25 | 2020-03-20 | 上海欣峰制药有限公司 | Cefoperazone sodium and sulbactam sodium powder injection for injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101284009A (en) * | 2008-05-29 | 2008-10-15 | 管小明 | Cefoperazone sodium and sulbactam sodium combination and preparation method thereof |
| CN102462684A (en) * | 2010-11-10 | 2012-05-23 | 湘北威尔曼制药股份有限公司 | Medicinal composition consisting of ceftriaxone sodium and sulbactam sodium and preparation method thereof |
| CN110893232A (en) * | 2019-09-25 | 2020-03-20 | 上海欣峰制药有限公司 | Cefoperazone sodium and sulbactam sodium powder injection for injection and preparation method thereof |
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